Velopharyngeal insufficiency after cleft palate repair in patients with isolated Robin sequence versus isolated cleft palate: A systematic review

Background: Robin sequence (RS) is characterized by micrognathia, glossoptosis, and upper airway obstruction, and is often combined with a cleft palate. It is unclear whether RS negatively impacts the development of velopharyngeal incompetence (VPI) and attainable speech outcomes. This study systematically reviewed speech outcomes in patients with cleft and isolated RS (IRS) compared with only isolated cleft palate (ICP). Methods: A literature search following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines was performed using the PubMed and EMBASE databases. Articles reporting speech outcomes following primary palatoplasty in patients with IRS only or IRS versus ICP were identified. Study characteristics and methods, primary- and VPI palatoplasty, speech measurements, and post-operative complications were collected. Primary outcomes included VPI and need for speech correcting surgery (SCS). Methodological quality was appraised using the methodological index for non-randomized studies (MINORS) criteria (range: 0-16 and 0-24). Results: Nineteen studies reported VPI event rates that varied between 14% and 88% for IRS and 0% and 62% for ICP. Five out of 8 studies (67%) comparing VPI event rates between IRS and ICP found no significant difference. SCS rates varied between 0% and 48% for IRS and 0% and 24% for ICP. Six out of 9 studies (67%) comparing SCS rates between IRS and ICP, found no significant difference. Combined VPI event rates were 36.1% for the IRS group and 26% for the ICP group, for SCS rates this was 20% for IRS and 13% for ICP. Conclusion: Most articles found no significant difference between the VPI and SCS rates indicating that speech outcomes might be similar in patients with IRS and ICP. To better compare these groups a standardized international protocol is needed.


Introduction
Robin sequence (RS) is a rare congenital anomaly characterized by the triad of micrognathia, glossoptosis, and varying degrees of upper airway obstruction.][3][4] RS encompasses a spectrum of presentations with varying degrees of complexity and clinical manifestations that directly impact speech development and outcomes.The distinction between isolated RS (IRS) and RS associated with syndromes or genetic mutations (SRS) is crucial for understanding the nuanced challenges in managing speech outcomes.RS-plus refers to a group of patients with RS and additional congenital anomalies or chromosomal defects, but without an identified associated syndrome.IRS typically presents without additional congenital anomalies beyond the RS triad, whereas SRS involves more complex genetic backgrounds and often includes other anomalies that can further complicate speech development. 56][7][8][9] The exact pathogenetic physiology of RS is still unknown, with the causes for IRS being unclear. 10 , 11In SRS, the pathological mechanism is defined by mutations in chromosomes and specific genes, but the causes for IRS are still unclear. 4 , 10 , 11t is thought that the retrognathic tongue position causes patients with RS to have a wider and U-shaped CP in patients with RS compared with the patients with isolated CP (ICP).This complicates primary palatoplasty and may influence the approach and outcomes of speech therapy. 5 , 12 , 13oreover, patients with RS can present with a varying degree of pulmonary and cardiac complications due to upper airway obstructions. 5 , 14 , 15The heterogeneity within the RS population, including patients with RS-plus, necessitates individualized management plans to address the unique combination of airway, feeding, and speech challenges.The additional burden of pulmonary and cardiac complications in patients with RS further complicates the clinical picture, potentially affecting speech therapy outcomes owing to the intertwined nature of respiratory and speech mechanisms.Feeding difficulties and reflux are also common symptoms, resulting in reduced weight gain and possible failure to thrive. 5 , 14 , 15Mortality rates vary between 1% and 26% and are mainly caused by respiratory insufficiency in combination with neurological or cardiological anomalies. 5 , 168][19][20] Clinical manifestations of VPI, such as hypernasality, nasal air emission, and an inability to produce pressure consonants, affect speech development and can result in speech and language delays.Given the critical role of speech in social integration and psychological health, understanding the distinct pathophysiology and clinical implications of RS versus ICP is essential for tailoring interventions. 17-19 , 21This nuanced approach aimed to optimize speech development outcomes by recognizing that the complexity of RS may require more specialized therapeutic strategies compared to ICP.
It is important to distinguish between IRS and SRS for clinical practices, as treatment is likely to differ. 11Sur gical intervention for CP repair is essential for resolving feeding and hearing difficulties, minimizing facial growth disturbances, and establishing a competent velopharyngeal sphincter to achieve proper speech development.3][24][25] However, the timing of palatoplasty in patients with RS may be delayed due to upper airway and feeding difficulties, depending on the patient's response management regarding these issues.This delay in surgical intervention can have a direct effect on speech development and outcomes, as the establishment of proper velopharyngeal function is crucial for speech articulation and intelligibility. 24 , 26he persistence of VPI after primary palatoplasty and speech correction surgery (SCS) is a significant concern in the management of patients with CP. 18 , 20 VPI after primary palatoplasty requires intensive follow-up and practice by a speech and language pathologist. 4 , 11 , 22 , 27-29Approximately 6% to 19% of primary palatoplasties require SCS during follow-up. 30Despite efforts to standardize speech assessment methods, a gold standard is still lacking, complicating the decision-making process for performing SCS, which currently relies on expert opinions and shared decision-making. 31 , 32ome studies theorize that patients with IRS have an intrinsically normal palatal development, whereas the cause of CP in patients with ICP might be intrinsically aberrant, due to multifactorial genetic and environmental factors. 33 , 34Therefore, patients with IRS might have a better velopharyngeal function after primary palatoplasty, resulting in better speech outcomes than patients with ICP. 33 , 34ontrary to this theory, other studies suggest that after primary palatoplasty of a wide U-shaped cleft, a lack of tissue and scarring might result in a short and immobile velum, causing worse speech outcomes in patients with IRS compared to patients with ICP. 35 , 36he varying degrees of airway obstruction and congenital anomalies, bring unique challenges in the treatment of patients with RS.Several studies have focused on the treatment of RS on mandibular development, airway obstruction, and feeding problems, but few studies have compared speech outcomes of patients with RS and ICP. 4,35 , 37 , 38o far, a single systematic review by Wan et al. (2015), compared speech outcomes after primary palatoplasty in patients with IRS and ICP.They suggested a tendency toward slightly worse speech outcomes in patients with IRS, but no significant difference was found. 39The review included a limited number of studies, among which half of them did not clearly provide data on speech outcomes of IRS alone. 39Overall, Wan et al. (2015) mentioned that the included articles provided controversial and insufficient data for drawing decisive conclusions. 39Hence, it is still unclear if the presence of RS negatively impacts attainable speech outcomes in infants with CPs. 4,35 , 38-40his study investigated whether patients with IRS have higher incidences of VPI or SCS after primary palatoplasty compared to patients with ICP, by systematically reviewing the currently available literature.

Methods
This review was conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.
On December 1, 2023, a systematic computer-based search was performed using predefined criteria.Data were obtained from PubMed and EMBASE.The search strategy, performed by 2 independent researchers, included the following terms "Pierre Robin syndrome" and "cleft palate" and is described in detail in Supplemental Data Content 1. Inclusion criteria included: Randomized controlled trial or cohort studies, clear provision of data on speech outcomes, and 3 to 6 years of age at speech assessment.Exclusion criteria included: SRS only and articulation errors only (Supplemental Data Content 2).Additional articles were obtained from the reference lists of the previously selected articles.These articles were screened for eligibility in a similar matter.
All available data were organized and analyzed in Microsoft Excel v2207 (Microsoft Corporation (2022).Microsoft Excel.Retrieved from https://office.microsoft.com/excel ).Data extracted were inclusion-exclusion criteria, study objective, genetic screening for RS, timing, type and allocation of primary surgery, number of surgeons, timing of speech evaluations and speech methods, indications, and type of SCS and other outcomes mentioned in the articles.In addition, if available, data on cleft characteristics regarding CP measurements (length and width) or CP classification were added.Further data extracted included VPI, hypernasality, need for SCS, oral nasal fistula (ONF), ONF surgery and obstructive sleep apnea (OSA).Critical appraisal of the quality of the selected studies was performed using the methodological index for non-randomized studies (MINORS). 41s speech measurements methods are difficult to compare, the choice was made to focus on VPI and SCS as a comparison tool for speech outcomes between the different studies from different countries.
Studies were rated on VPI as a dichotomous outcome.All speech measurements, subjective and objective, that scored general presence of VPI (mild, moderate, and severe), presence of hypernasality (mild, moderate, and severe), measurements concerning borderline-incompetent to incompetent, incompetent, and highly incompetent were considered as VPI present.If several scoring systems for VPI were used, the highest score was used in this review.In case the article mentioned a gold standard, this score was used. 25ata were analyzed using IBM SPSS (IBM Corp. Released 2021.IBM SPSS Statistics for Windows, Version 28.0.Armonk, NY: IBM Corp).Binomial proportion confidence intervals were calculated using the Clipper-Pearson method.Comparison of the proportions was carried out using the chi-squared or Fisher's exact tests.Odds ratios were calculated and were displayed in a mean with a 95% confidence interval.A p-value < 0.05 was considered significant.

Results
The initial search yielded in a total of 1717 articles.After removal of duplicates, 1388 articles were screened based on title and abstract.Application of inclusion and exclusion criteria resulted in 42 articles eligible for full-text retrieval, among which 19 were included.Reference list screening identified an additional 16 articles that were not found in the initial database search.After reviewing these articles, no additional articles were added through the reference.Reasons for exclusion of articles are demonstrated in Supplemental Data Content 2.

Primary outcomes VPI event rates
46,47 Calculations on VPI event rates regarding IRS were performed on 10 studies ( Table 3 and Figure 1 ).A total of 308 out of 914 patients with IRS showed signs of VPI varying from 13.6% to 69.8%.Six studies examined VPI event rates concerning IRS versus ICP.VPI was present in   3% -U = unclear, art p = p-value stated in article, calc p = calculated p-value, * = significant difference with p < 0.05.As none of the articles matched the experimental and control groups, and there was too much heterogeneity, it was not possible to statistically compare the total sum of the event rates.art p = p-value stated in article, calc p = calculated p-value, * = significant difference with p < 0.05.As none of the articles matched the experimental and control groups, and there was too much heterogeneity, it was not possible to statistically compare the total sum of the event rates.

SCS event rates
Six out of 9 studies (66.7%) comparing SCS rates between IRS and ICP groups, found no significant difference. 35,42,44,47,48As shown in Table 4 , 16 studies allowed calculations for patients with IRS, resulting in a total of 187 out of 952 patients with IRS having SCS for VPI.Event rates varied between 0% and 47.6% among studies, with an combined effect rate of 19.6% (17.2%-22.3%).In 9 studies presenting data on SCS in patients with ICP (when compared with patients with IRS), rates varied between 0.0% and 23.8%, with a total of 128 out of 985 patients with ICP.The combined effect was 13.0% (11.0%-15.3%).
Finally, data on OSA were provided in 4 studies, 33 , 37 , 44,50 and 1 study mentioned respiratory distress. 44See Supplemental Data Content 4 for more details on OSA.

Discussion
Patients with CP are at risk for developing VPI, possibly negatively impacting a child's speech development, and causing a serious burden on the patient and their family. 17-19 , 21,35To date, the impact of RS on speech prognosis concerning VPI remains unclear. 4Few articles have been published comparing speech outcomes in patients with IRS and ICP.This study was designed to systematically review current literature on speech outcomes after primary palatoplasty in patients with IRS and ICP and to investigate whether the presence of RS negatively impacts speech outcomes regarding VPI.The combined event rates of VPI and SCS were higher among patients with IRS than in patients with ICP.However, most articles found no significant difference between the 2 groups.Wan et al. (2015) systematically reviewed the literature and found no significant differences between patients with IRS and ICP regarding speech outcomes. 39It is unclear whether only data on patients with IRS were included in this review.They mentioned 5 studies providing data on VPI, among which 3 were excluded from this study owing to unclear data on speech outcomes. 25 , 36 , 52urthermore, they did not appear to make a clear distinction between IRS and SRS.Moreover, study selection and data collection were not blinded between the 2 reviewers, possibly creating a selection bias.The present review highlights an extensive heterogeneity in clinical setting and calculated outcomes, similar to Wan et al (2015), making the interpretation of compared events rates difficult to interpret.
The included studies showed mixed results regarding VPI and SCS rates.Only 3 studies found a significant difference in VPI event rates between IRS and ICP. 38 , 48,49Furthermore, 2 studies described a significant difference in SCS rate, with a range of event rates from 2.3% to 19.4%. 9 , 40Interestingly, Chorney et al. 2016, did not describe a significant difference; however, using their data we found a significant difference. 45SCS technique differed in the studies, pharyngeal flaps and Furlow's Z-plasty were the most common used interventions.SCS is considered necessary in 6% to 19% of patients with CP and must be deliberately chosen by considering cleft characteristics and the patient's physical and psychological wellbeing. 30,35 , 37Furthermore, the decision to proceed with SCS varies greatly depending on several factors, including the patient's condition, clinician's assessment, speech assessment, and surgeon's expertise.Consequently, it may not be a completely reliable outcome measure for evaluating VPI.
Although 2 studies showed a significant difference in VPI development based on cleft width and classification, 44 , 53 others found no significant difference. 9 , 21 , 32 , 36There is no established gold standard for primary palatoplasty.Various surgical techniques such as Z-plasties and various different straightline techniques have been used.It is often unknown whether radical dissection was performed or if a microscope was used during the palatoplasty.Straight-line techniques are associated with midline scarring and do not lengthen the soft palate. 54Interestingly, there was no significant difference in VPI outcomes between the techniques.Overall, a preferred technique for improving speech outcomes in patients with CP could not be selected based on the available data.Moreover, the lack of stratification for cleft severity in several of the reviewed studies constitutes a major confounding factor that could significantly skew the results and interpretations of the study.Various methods were employed to assess speech, yet not every study disclosed its specific approach for speech evaluation. 9,35 , 50The utilization of objective measures for VPI, such as videofluoroscopy or nasopharyngoscopy, is notably underreported.Although it is often recommended to assess speech before the age of 5 years, this guideline was not universally followed across the studies. 24,48he timing and frequency of evaluations are crucial, as the outcomes of speech testing can be affected by factors such as the patient's motivation, fatigue, and psychological state.Although speech therapy was implemented in 7 studies, 9,35,37,38,42,46,47,50 its precise impact remains unclear and warrants further investigation.The absence of standardized speech testing methods likely contributes to, and may indeed be the primary cause of, the significant heterogeneity observed among the included articles.
The timing of primary palatoplasty exhibits considerable variation across studies, underscoring the ongoing debate regarding the most advantageous period for CP closure.Although earlier surgical intervention is generally linked to enhanced speech outcomes, the formation of surgical scar tissue following CP repair can potentially impede maxillary growth, leading to craniofacial anomalies. 55Furthermore, a significant body of research has explored the efficacy of a two-stage repair approach.However, this strategy has been implicated in less favorable long-term speech outcomes. 32 , 40The substantial heterogeneity observed in speech outcomes across all included articles in the study indicates that the relationship between surgical timing, technique, and speech development outcomes remains complex and multifaceted, necessitating further investigation to establish optimal treatment protocols.
The accurate diagnosis and differentiation IRS and SRS are critical for the assessment and treatment of VPI, as the etiology and management may differ significantly between the 2 conditions.In the current literature, there is a lack of consensus regarding the impact of syndromes on the incidence of VPI, with some studies reporting no significant difference between IRS and SRS, whereas others have observed notable disparities. 11This inconsistency may be attributed, in part, to the absence of genetic screening in 10 of the studies reviewed, 9,21,33,35,37,38,40,48,50 which could lead to the inadvertent inclusion of undiagnosed syndromic cases within the IRS group.The omission of genetic screening hinders the precise categorization of patients, potentially conflating IRS with SRS and contributing to the observed heterogeneity in VPI event rates. 49 , 56However, the influence of syndromes on VPI remains unclear, with some studies finding no significant difference in VPI incidence between IRS and SRS, 37,42,[44][45][46] while others finding a significant difference. 32 , 33Genetic screening plays a pivotal role in accurately distinguishing between IRS and SRS, ensuring that patients are correctly classified, which is essential for understanding the true incidence of VPI and tailoring appropriate treatment strategies.Therefore, incorporating genetic screening into the diagnostic process is indispensable for advancing our comprehension of VPI in the context of RS and for the development of more effective clinical protocols.
Regarding OSA, there is insufficient data to make conclusive statements. 9 , 45Previous literature has outlined various perioperative protocols, including the use of standard polysomnography, to monitor these patients effectively. 16,27,44 , 57 , 58This gap in accurate ONF reporting underscores the need for more rigorous and transparent documentation of surgical outcomes to better understand and mitigate the risks associated with CP repair.
The current review has several strengths, including being the largest series of studies that provide data on VPI and SCS rates in individuals with IRS.The study methodology and patient characteristics are presented in detail, facilitating comparisons.However, there are limitations to be acknowledged.The broad search strategy aimed to minimize selection bias but resulted in heterogeneity.All but one study had a retrospective design, possibly leading to selection bias.Although hearing outcomes are an important outcome in relation to speech outcomes, this was not within the scope of our review; therefore, we did not review this subject.We only included studies involving patients with ICP if they also included patients with RS, possibly leading to underreporting and observer bias.Nonstandardized operating techniques created a bias, possibly impacting speech outcomes.Relevant data, such as cleft characteristics and VPI severity, were incompletely reported.Finally, the study did not focus on the outcomes of SCS.
This systematic review has uncovered a significant degree of heterogeneity in the reported speech outcomes among patients with IRS, which has precluded the effective use of traditional meta-analysis and multivariate analysis techniques.Despite this variability, the largest studies included in the review identified significant differences in VPI rates between the patients with IRS and ICP, suggesting that there may indeed be a distinction in speech outcomes between these groups.However, to draw definitive conclusions, further research is imperative.The establishment of an international, multidisciplinary protocol for CP management is essential to enhance the consistency and quality of cleft care globally.Such a protocol should encompass standardized approaches to palatoplasty, SCS, genetic screening, cleft measurements, and speech testing.Future investigations should delve into the influence of speech therapy, SCS, airway management, and hearing status on speech outcomes.These studies should employ multicenter prospective designs with blinded speech assessments and an intentionto-treat analysis framework.Additionally, research efforts should be directed toward elucidating the pathophysiological differences between CP and RS to better understand their impact on VPI and associated speech outcomes.

Conclusions
The majority of the included articles did not report a significant difference in speech outcomes between patients with IRS and ICP, suggesting that speech outcomes in patients with IRS may be comparable with those in patients with ICP.To enhance the consistency of future research, the implementation of an international standard protocol for CP treatment and assessment is essential.Figure 2 .

Financial disclosure
No funding was received for conducting this review.

Table 1
Baseline characteristics of all included studies.

Table 1 (
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Table 1 (
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Table 2
Characteristics of study population.

Table 4
SCS rates.= significant difference with p < 0.05.As none of the articles matched the experimental and control groups, and there was too much heterogeneity, it was not possible to statistically compare the total sum of the event rates.
art p = p-value stated in article, calc p = calculated p-value, *